2型糖尿病患者微血管病变与血液流变学变化、胰岛素抵抗的相关性

目的 :研究血液流变学变化和胰岛素抵抗与 2型糖尿病微血管病变的关系。方法 :检测 10 6例 2型糖尿病患者 ,其中有微血管并发症 5 3例 ,无微血管并发症 5 3例 ,以及 5 3例正常对照组的血液流变学、空腹血糖、空腹胰岛素 ,计算胰岛素敏感性指数 (ISI) ,并进行比较。结果 :糖尿病两组全血粘度和血浆粘度均显著高于正常对照组 ;ISI则显著低于正常对照组 (P<0 .0 1)。糖尿病有微血管病变组全血粘度和血浆粘度显著高于无微血管病变组 ;ISI显著低于无微血管病变组 (P<0 .0 1)。多元逐步回归分析显示 ,2型糖尿病微血管病变与糖尿病病程、血糖、全血粘度和血浆粘度呈显著正相关 (r=0 .62 4,0 .42 8,0 .3 46,0 .3 82 ,P值分别 <0 .0 0 1,0 .0 1,0 .0 5 ,0 .0 1) ,与 ISI呈显著负相关 (r=-0 .3 5 2 ,P<0 .0 5 )。结论 :2型糖尿病微血管病变患者存在持续性的高血糖、高血液粘度 ,糖尿病病程的延长 ,严重的胰岛素抵抗为 2型糖尿病微血管病变的主要危险因素。     

持续皮下胰岛素输注与多次胰岛素皮下注射对2型糖尿病强化治疗的效果比较

目的比较持续皮下胰岛素输注(CSII)和多次胰岛素皮下注射(MSII)在2型糖尿病强化降糖中的效果。方法将48例2型糖尿病患者随机分成CSII组(n=26)和MSII组(n=22)两组,CSII组的患者采用胰岛素泵降糖治疗,MSII组的患者采用胰岛素笔降糖治疗。监测两组患者治疗前后全天血糖谱的变化,观察并比较血糖达标所需要的时间、胰岛素用量、低血糖发生率等情况。结果CSII组与MSII组相比,血糖达标所需的时间、胰岛素用量及低血糖发生率等差异有显著统计学意义(P<0.01)。结论持续皮下胰岛素输注和多次胰岛素皮下注射对2型糖尿病患者强化降糖治疗均有效,但胰岛素泵降糖效果优于胰岛素笔。     

Mitochondrial dysfunction and type 2 diabetes

Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic beta cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.     

Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes

Endoplasmic reticulum (ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.     

Biomedicine. New insights into type 2 diabetes

Researchers studying type 2 diabetes are optimistic that they are closing in on the elusive causes of the world's most prevalent metabolic disorder--although no one is willing to bet the bank on it. Using both biochemical and genetic approaches, diabetes researchers have identified multiple intracellular signaling pathways that appear to lie at the heart of this condition, which affects some 250 million people worldwide and is the leading cause of blindness, kidney failure, and amputation among adults. And in the process, they have thrown out much of the dogma of the past 10 years.     

The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy

Epithelial cells respond to physicochemical damage with up-regulation of major histocompatibility complex-like ligands that can activate the cytolytic potential of neighboring intraepithelial T cells by binding the activating receptor, NKG2D. The systemic implications of this lymphoid stress-surveillance response, however, are unknown. We found that antigens encountered at the same time as cutaneous epithelial stress induced strong primary and secondary systemic, T helper 2 (T(H)2)-associated atopic responses in mice. These responses required NKG2D-dependent communication between dysregulated epithelial cells and tissue-associated lymphoid cells. These data are germane to uncertainty over the afferent induction of T(H)2 responses and provide a molecular framework for considering atopy as an important component of the response to tissue damage and carcinogenesis.     

影响二甲双胍初治2型糖尿病效果因素分析

目的 调查常见几种影响二甲双胍治疗2型糖尿病的因素,为使用二甲双胍初治2型糖尿病提供依据。方法 以初诊的117例2型糖尿病患者作为研究对象,对影响二甲双胍初治2型糖尿病效果进行评估。选择年龄、性别、体质量指数(BMI)、血压、空腹血糖(FBG)、餐后2 h血糖(2hPG)、空腹胰岛素(FINS)、糖化血红蛋白(HbA₁C)、总胆固醇(TC)和胰岛素抵抗指数(HOMA-IR)等因素进行分组考查,比较各组中二甲双胍初治疗效的差异性。结果 经二甲双胍初治3个月后,BMI、FBG、2hPG、FINS、HbA₁C和TC水平均明显下降,较治疗前均差异有统计学意义(P＜0.05)。FINS和HOMA-IR等因素对二甲双胍初治2型糖尿病的影响显著(P＜0.05)。结论 FINS和HOMA-IR可能是影响二甲双胍初治2型糖尿病疗效的重要因素。     

Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels

New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D-in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1-and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.     

A family with severe insulin resistance and diabetes due to a mutation in AKT2

Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.     

Diabetes, obesity, and the brain

Recent evidence suggests a key role for the brain in the control of both body fat content and glucose metabolism. Neuronal systems that regulate energy intake, energy expenditure, and endogenous glucose production sense and respond to input from hormonal and nutrient-related signals that convey information regarding both body energy stores and current energy availability. In response to this input, adaptive changes occur that promote energy homeostasis and the maintenance of blood glucose levels in the normal range. Defects in this control system are implicated in the link between obesity and type 2 diabetes.     

2型糖尿病血管病变时血浆利钠肽水平的变化及临床意义

目的观察血浆心房利钠肽(ANP)、脑利钠肽(BNP)、C型利钠肽(CNP)水平在2型糖尿病血管病变时的变化及临床意义。方法应用酶联免疫法(ELISA)测定正常对照组(25例)、2型糖尿病无血管病变组(28例)及2型糖尿病血管病变组(20例)血浆ANP、BNP及CNP的水平,分析各组间血浆三个指标水平的变化。结果2型糖尿病血管病变组血浆ANP、BNP水平明显高于另外2组(P<0.01),而血浆CNP则明显降低(P<0.01)。结论血浆ANP、BNP及CNP的联合检测可作为简便、价廉、可靠的糖尿病血管病变的筛选指标。     

A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.     

产PVL金黄色葡萄球菌对奶牛乳腺上皮细胞内质网应激和自噬的影响

【目的】研究产PV-杀白细胞素（Panton Valentine leukocidin,PVL）金黄色葡萄球菌ATCC49775（产PVL标准菌株）、ΔPVL 49775（PVL基因缺失株）以及体外重组PVL（rPVL）对奶牛乳腺上皮细胞（bovine mammary epithelial cells,BMECs）内质网应激和自噬的影响,为系统阐述金黄色葡萄球菌及PVL对BMECs损伤的分子机制奠定基础。【方法】用感染复数（MOI）为30的金黄色葡萄球菌菌株ATCC49775和ΔPVL 49775感染BMECs,于感染后3和6 h取样;用100 ng/mL rPVL处理BMECs,于处理后1,3和6 h取样;以未处理的BMECs为对照（CK）。用免疫荧光法检测样品BMECs细胞的自噬体荧光强度;提取样品细胞的总蛋白,以GADPH为内参蛋白,采用Western blot法检测各处理组内质网应激相关蛋白（CHOP和GRP78）和自噬相关蛋白（LC3 Ⅱ、ATG5、Beclin1和p62）的相对表达量。【结果】ATCC49775、ΔPVL 49775感染后不同时间,BMECs自噬体荧光强度均极显著（P＜0.01）高于CK,内质网应激相关蛋白（CHOP和GRP78）和自噬相关蛋白（LC3-Ⅱ、ATG5、Beclin1和p62）的表达水平也大多显著(P<0.05)或极显著（P＜0.01）高于CK;同一处理时间下, ATCC49775感染组自噬体荧光强度和相关蛋白表达水平均显著(P<0.05)或极显著（P＜0.01）高于ΔPVL49775感染组。 rPVL处理后不同时间,BMECs的自噬体荧光强度均极显著（P＜0.01）高于CK,内质网应激和自噬相关蛋白的表达水平大多极显著（P＜0.01）高于CK。【结论】产PVL金黄色葡萄球菌ATCC49775、ΔPVL 49775以及rPVL均加剧了BMECs的内质网应激和自噬,说明PVL在金黄色葡萄球菌感染BMECs的过程中有重要作用。